ABSTRACT Breast cancer is the number two cause of death among all types of cancers in women. The deadliest subtype of breast cancer, triple-negative, carries the highest metastatic risk and poorest outcome due to the resistance to current therapeutic methods. Triple-negative breast cancer (TNBC) is an intrinsically heterogeneous disease. Targeting single biomarker or oncogene often yields unsatisfactory therapeutic outcome in TNBC treatment. To achieve a broader therapeutic benefit, our starting point is copper ion, one critical metal ion that plays irreplaceable roles in a broad range of biochemical reactions. Copper excess in serum and cancerous tissues has been long recognized in breast cancer patients. Dysregulation of copper metalloproteins is found to be involved in uncontrolled growth, invasion, dissemination of cancer cells, angiogenesis and secondary tumor formation at distant sites. Despite the well-recognized importance, successful attempts to treat cancer with copper chelation are rather limited. This project aims to establish a self-reporting copper depletion nanoplatform to effectively deplete copper in TNBC and ultimately inhibit primary tumor progression and metastasis formation. This application is tightly aligned with the program scope of the Innovative Research in Cancer Nanotechnology (IRCN) Initiative with the goal to employ a novel nanotechnology-based approach to understand copper's role in breast cancer biology systematically and to develop a powerful theranostic drug for TNBC patients. We will design copper- depleting nanocomplex with high depleting efficiency, low toxicity and self-reporting function as TNBC theranostics (Aim 1), determine the treatment effect of copper-depleting nanocomplex and identify the therapeutic mechanism in vitro (Aim 2), and define the therapeutic efficacy of copper-depleting nanocomplex for primary and metastatic TNBC tumor models (Aim 3).